Receipt of prescription opioid medication is associated with increased mortality in an Israeli population.

BACKGROUND: Despite Israel's increased use of prescription opioids, reported deaths resulting or associated with opioids have decreased, in fact dramatically, since 2005. This contrast is unique and difficult to explain. We sought to examine whether higher prescribed opioid dosages among adults without oncologic diagnoses were associated with higher all-cause mortality rates. METHODS: A historical cohort study in Clalit Health Services, using a data repository including all adult patients prescribed opiates between 2010 and 2020, excluding patients with oncologic diagnoses. Patients were classified into three groups according to opioid use: below 50 Morphine milligram equivalents (MME) per day, 50 to 90 MME per day, and above 90 MME per day. Sex, Charlson comorbidity score, age and socioeconomic status were recorded. Mortality rates were compared between the dosage groups and compared to age-standardized mortality rates in the general population. RESULTS: On multivariate analysis, patients receiving 90 or more MME per day were 2.37 (95%CI 2.1 to 2.68) more likely to have died compared to patients receiving below 50 MME per day. The respective hazard ratio among patients receiving between 50 and 90 MME per day was 2.23 (2.01 to 2.46). Among patients aged 18 to 50, standardized mortality ratios (SMRs) compared to the general population ranged between 5.4 to 8.6 among women, receiving between 50 and 90 MME per day, and between 8.07 and 10.7 among women receiving 90 or more MME per day. The respective SMRs among men were 1.2 to 3.8 and 2.7 to 5.4. CONCLUSION: Increased opioid use is independently associated with increased all-cause mortality among non-oncological patients. This result is most notable among young adults with little or no known comorbidities. These findings are consistent with results in other countries and seem more credible than previous Israeli reports. Healthcare regulators and providers should, therefore, act to curtail the increasing opioid prescriptions and devise and enhance controls in the healthcare system, which, until 2020, had very limited mechanisms in place.

Serological follow-up after syphilis diagnosis in Israel.

The global incidence of syphilis is increasing. Continuity of care challenges the control of sexually transmitted diseases. In this study, we assessed the follow-up and serological decline differences between community- and hospital-diagnosed patients in Israel. A historical cohort study was conducted using the Israel National Syphilis Center (NSC) repository. Patients with a positive non-specific Venereal Disease Research Laboratory (VDRL) test between 2011 and 2020 were included. Rates of serological follow-up and serological titre decreases were compared between hospital- and community-diagnosed patients. The study included 4,445 patients, 2,596 (58.4%) were diagnosed in community clinics and 1,849 (41.6%) in hospitals. Of community-diagnosed patients, 1,957 (75.4%) performed follow-up testing, compared with 834 (51.2%) hospital-diagnosed patients (p < 0.001). On multivariate analysis, the odds ratio of serology follow-up among community-diagnosed patients was 2.8 (95 per cent confidence interval (95% CI): 2.2-3.5) that of hospital-diagnosed patients. There were 1,397 (71.4%) community-diagnosed patients with serological titre decrease, compared with 626 (74.9%) hospital-diagnosed patients (p = 0.03). On multivariate analysis, this difference diminished. Serological follow-up testing is suboptimal and was performed more often among patients initially diagnosed in the community compared to hospitals. Continuity of care should be improved to promote successful patient care and prevent disease spread.

Gradual dosing of ursodeoxycholic acid in mothers with intrahepatic cholestasis of pregnancy may improve composite neonatal outcome.

INTRODUCTION AND OBJECTIVES: Intrahepatic cholestasis of pregnancy (ICP) is often accompanied by fetal and maternal complications. MATERIALS AND METHODS: Retrospective review of the clinical course of women with ICP and their neonates treated at our medical center over a 10-year period. Special attention was paid to the maternal and neonatal response to 2 different modes of ursodeoxycholic acid (UDCA) administration. RESULTS: Neonates of mothers with high total bile acid levels had a poorer composite neonatal outcome. Twenty-seven women who presented at an advanced stage of their pregnancies did not receive UDCA. UDCA was administered in 2 modes: either a full dose at admission (76 women) or a gradually increasing dose until the desired dosage was reached (25 women). The mean gestational age at delivery for the 94 neonates that were exposed to full UDCA dose was the lowest (36±2.3 weeks for the full dose, 37±1.4 weeks for the 30 neonates from the gradually increasing dose, 38±1.6 weeks for the 29 neonates from the no treatment group, p<0.001). The group of neonates that were exposed to full UDCA dose had the highest rate of unfavorable composite neonatal outcome (53% for full dose, 30% for gradually increasing dose, 24% for the no treatment group, p=0.006). CONCLUSIONS: Compared to the administration of a full UDCA dose, the administration of a gradually increasing dose of UDCA may be associated with a greater gestational age at delivery and fewer events of unfavorable composite neonatal outcomes. These novel findings should be retested prospectively in a large cohort of patients.

Trends in Israeli community-based opioid prescribing, 2010-2020, an observational study of the country's largest HMO.

BACKGROUND: Prescription opioids are widely used for pain control and palliative care but have been associated with a variety of untoward effects, including opioid use disorder, addiction, and increased mortality. Patterns of opioid use in Israel are to date poorly described. METHODS: Using a community-based database, the authors performed a retrospective analysis of filled opioid prescriptions of Israeli HMO members 18 years of age or older during the years of 2010-2020 that filled at least one opioid prescription. Morphine milligram equivalent (MME) calculations were stratified by presence or absence of oncology diagnosis and by specific opioid medication. RESULTS: The percentage of HMO members who filled at least one opioid prescription increased every year from 2.1% in 2010 to 4.2% in 2020. There was an increase in the MME per prescription (44.2%), daily MME per capita (142.1%) and MME per prescription-filling patient (39%) from 2010 to 2020. Increased prescription opioid use is driven by a small group of non-oncological patients, which is less than 1.5% of opioid-prescribed patients and 0.1% of the adult population, primarily owing to fentanyl use. CONCLUSION: Supervision and control of opioid prescriptions in Israel should be a focused effort directed at patients prescribed uniquely high dosages rather than a population-wide strategy that focuses on all patients prescribed opioids. This should be complemented by improved physician training and access to non-opioid therapies, as well as improved data collection and analysis.

Incidence of Invasive Infections Among Hemato-Oncology Patients with Significant Burden of Candida in Stool.

Candidemia is a serious infection associated with increased mortality. It is unclear whether a high concentration of Candida in stool in patients with hematologic malignancies is associated with a higher risk for developing candidemia. In this observational historical study in patients hospitalized in hemato-oncology departments, we describe the association between gastrointestinal Candida colonization and the risk for candidemia and other severe outcomes. Data from 166 patients with heavy burden of Candida in stool were collected and compared to a control group of 309 patients with minimal or no Candida in stool, from 2005 to 2020. Severe immunosuppression and recent use of antibiotics were more common in heavily colonized patients. Outcomes of heavily colonized patients were worse as compared to the control group with statistical significance in 1-year mortality (53% vs. 37.5%, p = 0.001) and borderline statistical significance in candidemia rate (12.6% vs. 7.1%, p = 0.07). Risk factors for 1-year mortality were significant colonization of Candida in stool, older age and recent use of antibiotics. In conclusion, significant stool burden of Candida among hospitalized hemato-oncology patients may pose a risk for 1-year mortality and increased candidemia rate.

Sources of primary bloodstream infections in internal medicine patients - a cohort study.

PURPOSE: To describe the sources of bloodstream infections (BSIs) in internal-medicine patients, on admission and during hospitalization, and to determine the proportion of BSIs in which no secondary cause could be defined (i.e., primary-BSI). METHODS: We analyzed all BSIs at the internal-medicine wards of the two campuses of the Hadassah Hebrew-University Medical Center, during 2017-2018. We defined the BSI source of each event (secondary, Central-line associated BSI (CLABSI) or primary non-CLABSI) and compared BSIs present on admission (POA) to hospital acquired (HA). RESULTS: There were 595 patient-unique BSI events, 316 (53.1%) POA-BSI and 279 (46.9%) HA-BSI. Overall, 309 (51.9%) were secondary, 194 (32.6%) primary non-CLABSI and 92 (15.5%) CLABSI. Primary non-CLABSI in the POA-BSI group was 20.6% vs. 46.2% in the HA-BSI group (p = 0.001). The length of hospital stay (LOS) of the HA-BSI group was longer than in the POA-BSI group (mean LOS, 19 days vs. 13.6 days, p = 0.01) and mortality rate was higher (48.7% vs. 19%, p = 0.001). Staphylococcus aureus was more common in primary non-CLABSI than in CLABSI and secondary BSI (29.5%, 12.8% and 16.2%, respectively). CONCLUSIONS: The proportion of primary non-CLABSI among HA-BSI events is very high (46.2%). The absence of any plausible source for these BSIs, and the fact that in our hospital more than 90% of patients in medicine wards have peripheral lines, suggests that these may be a possible source for primary non-CLABSIs. Measures to prevent peripheral-line associated BSI (PLABSI), like those implemented successfully for the prevention of CLABSI, should be considered.

Real World Cost-Effectiveness Analysis of Population Screening for BRCA Variants among Ashkenazi Jews Compared with Family History-Based Strategies.

Identifying carriers of pathogenic BRCA1/BRCA2 variants reduces cancer morbidity and mortality through surveillance and prevention. We analyzed the cost-effectiveness of BRCA1/BRCA2 population screening (PS) in Ashkenazi Jews (AJ), for whom carrier rate is 2.5%, compared with two existing strategies: cascade testing (CT) in carrier's relatives (≥25% carrier probability) and international family history (IFH)-based guidelines (>10% probability). We used a decision analytic-model to estimate quality-adjusted life-years (QALY) gained, and incremental cost-effectiveness ratio for PS vs. alternative strategies. Analysis was conducted from payer-perspective, based on actual costs. Per 1000 women, the model predicted 21.6 QALYs gained, a lifetime decrease of three breast cancer (BC) and four ovarian cancer (OC) cases for PS vs. CT, and 6.3 QALYs gained, a lifetime decrease of 1 BC and 1 OC cases comparing PS vs. IFH. PS was less costly compared with CT (−3097 USD/QALY), and more costly than IFH (+42,261 USD/QALY), yet still cost-effective, from a public health policy perspective. Our results are robust to sensitivity analysis; PS was the most effective strategy in all analyses. PS is highly cost-effective, and the most effective screening strategy for breast and ovarian cancer prevention. BRCA testing should be available to all AJ women, irrespective of family history.

Association of Receiving a Fourth Dose of the BNT162b Vaccine With SARS-CoV-2 Infection Among Health Care Workers in Israel.

Importance: Despite the high 3-dose vaccination rate among health care workers (HCWs) in Israel, a high rate of SARS-CoV-2 breakthrough infections in this group was observed during the Omicron wave. As a result, the Israeli Ministry of Health decided to recommend a fourth vaccine dose to medical staff. Objective: To evaluate the benefit of a fourth BNT162b2 vaccine dose on the breakthrough infection rate among HCWs. Design, Setting, and Participants: This multicenter cohort study was performed in January 2022, the first month of the 4-dose vaccination campaign, during a surge of the Omicron variant wave. All health care workers at 11 general hospitals in Israel who had been vaccinated with 3 doses up to September 30, 2021, and had not contracted COVID-19 before the vaccination campaign were included. Exposures: Vaccination with a fourth dose of the BNT162b2 vaccine during January 2022. Main Outcomes and Measures: Breakthrough COVID-19 infections in 4-dose recipients vs 3-dose recipients measured by a polymerase chain reaction test result positive for SARS-CoV-2. Health care workers were tested based on symptoms or exposure. Results: A total of 29 611 Israeli HCWs (19 381 [65%] female; mean [SD] age, 44 [12] years) had received 3 vaccine doses between August and September 2021; of these, 5331 (18%) received the fourth dose in January 2022 and were not infected by the first week after vaccination. Overall breakthrough infection rates were 368 of 5331 (7%) in the 4-dose group and 4802 of 24280 (20%) in the 3-dose group (relative risk, 0.35; 95% CI, 0.32-0.39). Similar reductions were found in a matched analysis by the exact day of receiving the third vaccine (relative risk, 0.61; 95% CI, 0.54-0.71) and in a time-dependent Cox proportional hazards regression model (adjusted hazard ratio, 0.56; 95% CI, 0.50-0.63). In both groups, no severe disease or death occurred. Conclusions and Relevance: In this cohort study, the fourth BNT162b2 vaccine dose resulted in a reduced breakthrough infection rate among hospital staff. This reduction was lower than that observed after the third dose; nevertheless, considering the high infectivity of the Omicron variant, which led to critical medical staff shortages, a fourth vaccine dose should be considered to mitigate the infection rate among HCWs.

The Validity of Positive Coagulase-Negative Staphylococcus Cultures for the Diagnosis of Sepsis in the Neonatal Unit.

OBJECTIVE: Coagulase-negative Staphylococcus (CoNS) is the most frequent pathogen causing late-onset sepsis (LOS) in neonatal intensive care units (NICUs). Technical difficulties hinder blood culture (BC) collection and obtaining only one culture before initiating antibiotic therapy is a common practice. We sought to assess specific clinical information and CoNS cultures for the diagnosis of true bacteremia in the NICU. STUDY DESIGN: This historical cohort study was conducted in NICUs at the Hadassah-Hebrew University Medical Center of Jerusalem in Israel. Clinical and laboratory data in every CoNS bacteremia were collected and compared between bacteremia groups as follows: true positive, two positive BCs; contaminant, one positive BC out of two; undefined, one BC obtained and found positive. RESULTS: For 3.5 years, CoNS was isolated in 139 episodes. True positive was identified in 44 of 139 (31.7%), contaminant in 42 of 139 (30.2%), and the event was undefined in 53 of 139 (38.1%). Vancomycin treatment was more frequent in the true positive and undefined groups than the contaminant group (100, 90.6, and 73.8% respectively, p = 0.001); treatment was also prolonged in these two groups (p < 0.001). No clinical variables were associated with true bacteremia on multivariable analysis. CONCLUSION: Diagnosis should definitely be based on at least two positive BCs, despite objective difficulties in obtaining BCs in neonates. KEY POINTS: · CoNS is a frequent pathogen causing LOS in neonates.. · Due to technical difficulties, often only one culture is collected prior to antibiotic therapy.. · No clinical/laboratory variables were associated with the diagnosis of true CoNS bacteremia.. · Diagnosis should definitely be based on at least two positive BCs..

The effect of a third BNT162b2 vaccine on breakthrough infections in health care workers: a cohort analysis.

OBJECTIVES: In August 2021, 6 months after mass vaccination of the Israeli population with the two-dose BNT162b2 mRNA vaccine, a surge of coronavirus disease 2019 infections, mostly from the delta variant, appeared also among the vaccinated. In response, the Israeli Ministry of Health initiated a booster (third dose) vaccination program. We assessed the protective effect of the third dose among health care workers (HCWs). METHODS: Infections with severe acute respiratory syndrome coronavirus 2 are monitored systematically among HCWs at the Hadassah tertiary care medical centre in Jerusalem, Israel. In this cohort, we included breakthrough infections, defined as those occurring >180 days since the second vaccine dose. The follow-up period lasted 120 days. We compared infection rates between HCWs who received the booster dose and those who received only the two-dose regimen. RESULTS: The rate of breakthrough infections among HCWs who received only the two-dose regimen was 21.4% (85 of 398). The rate in the boosted group was 0.7% (35/4973; relative risk 30, 95% CI 20-50). Those results were seen in all age groups. DISCUSSION: The significantly lower rate of breakthrough infections in boosted HCWs indicates substantial protection by a third vaccine dose.

Invasive fungal infections in critically ill COVID-19 patients in a large tertiary university hospital in Israel.

An increasing number of studies have tried to determine the incidence of invasive fungal infections (IFIs) in COVID-19 patients. Challenges in the diagnosis of pulmonary aspergillosis in these patients have led to new definitions of COVID-19-associated pulmonary aspergillosis (CAPA). The aim of this study was to determine the incidence and outcomes of and risk factors for IFIs in critically-ill COVID-19 patients, using the new definitions, in a tertiary center in Israel. METHODS: A case-controlled study (from 1 September 2020 to 31 March 2021) in which data from COVID-19 critically-ill patients with a diagnosis of IFI were collected and compared to a control group without IFI. RESULTS: The incidence of IFI amongst 311 COVID-19 critically-ill patients was 6.1%. 3.5% had CAPA and 3.5% had candidemia. In-hospital mortality was higher amongst patients with IFI compared to those without IFI (89.4% vs 60%, p < 0.03). The most significant predictors of IFI were cardiovascular co-morbidity and carbapenem use. CONCLUSIONS: The low incidence of CAPA in our group of COVID-19 critically-ill patients was consistent with recent reports, underscoring the importance of differentiating between true infection and colonization. Awareness and timely diagnosis of IFIs in COVID-19 critically-ill patients are imperative considering the associated high mortality.

Increase in bone turnover markers in HIV patients treated with tenofovir disoproxil fumarate combined with raltegravir or efavirenz.

INTRODUCTION: Accelerated bone loss and osteoporosis are multifactorial comorbidities related to HIV and its treatments; however, their mechanisms remain elusive. Identifying HIV treatments that are differentially linked to osteoporosis risk, and clinical factors associated with HIV-related osteoporosis may enable optimizing anti-retroviral treatment (ART) and anti-osteoporosis therapy in preventing or treating this debilitating complication. This study aims to evaluate the dynamics of bone turnover markers after initiation of two commonly used antiretroviral regimens. METHODS: A prospective matched cohort study. Thirty treatment-naïve male patients (mean age 40 ± 10y) who initiated treatment with truvada (tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)) + raltegravir or TDF/FTC + efavirenz were included in the study. Control group included 15 treatment-naive HIV patients. Serum morning fasting level of P1NP and CTX were measured 0, 1, 6, and 12 months after treatment initiation in the two study groups, and at 0, 6 and 12 months in the control group. RESULTS: In both treatment groups, but not in the control group, both markers increased significantly over time with no difference in BTM between patients treated with raltegravir or efavirenz. Levels of P1NP were statistically higher at 6 and 12 months after treatment initiation in both treatment groups compared to the controls, while CTX during treatment increased in both treatment groups but was significantly higher only in the raltegravir treatment group after 12 months. The ratio of area under the curve of P1NP/CTX correlated with CD4 increment. CONCLUSIONS: Treatment initiation with raltegravir or efavirenz combined with TDF/FTC is associated with increased bone turnover. Thus, therapy that optimize bone turnover is needed to reduce bone loss at this vulnerable period and improve long-term bone health.

Is it financially beneficial for hospitals to prevent nosocomial infections?

BACKGROUND: Financial incentives represent a potential mechanism to encourage infection prevention by hospitals. In order to characterize the place of financial incentives, we investigated resource utilization and cost associated with hospital-acquired infections (HAI) and assessed the relative financial burden for hospital and insurer according to reimbursement policies. METHODS: We conducted a prospective matched case-control study over 18 months in a tertiary university medical center. Patients with central-line associated blood-stream infections (CLABSI), Clostridium difficile infection (CDI) or surgical site infections (SSI) were each matched to three control patients. Resource utilization, costs and reimbursement (per diem for CLABSI and CDI, diagnosis related group (DRG) reimbursement for SSI) were compared between patients and controls, from both the hospital and insurer perspective. RESULTS: HAIs were associated with increased resource consumption (more blood tests, imaging, antibiotic days, hospital days etc.). Direct costs were higher for cases vs. controls (CLABSI: $6400 vs. $2376 (p < 0.001), CDI: $1357 vs $733 (p = 0.047) and SSI: $6761 vs. $5860 (p < 0.001)). However as admissions were longer following CLABSI and CDI, costs per-day were non-significantly different (USD/day, cases vs. controls: CLABSI, 601 vs. 719, (p = 0.63); CDI, 101 vs. 93 (p = 0.5)). For CLABSI and CDI, reimbursement was per-diem and thus the financial burden ($14,608 and $5430 respectively) rested on the insurer, not the hospital. For SSI, as reimbursement was per procedure, costs rested primarily on the hospital rather than the insurer. CONCLUSION: Nosocomial infections are associated with both increased resource utilization and increased length of stay. Reimbursement strategy (per diem vs DRG) is the principal parameter affecting financial incentives to prevent hospital acquired infections and depends on the payer perspective. In the Israeli health care system, financial incentives are unlikely to represent a significant consideration in the prevention of CLABSI and CDI.

Chronic drug treatment among hemodialysis patients: a qualitative study of patients, nursing and medical staff attitudes and approaches.

BACKGROUND: Dialysis patients have a high pill burden, increasing their care complexity. A previous study in our institution's dialysis unit found notable discrepancies between medication prescriptions, purchases and patient reports of medication use: overall adherence to medication was 57%, on average; staff reported patients took 3.1 more medication types than actual purchases; concordance of patient purchases and nurse reports was found in 5.7 out of 23.6 months of patient follow-up. We sought to investigate patients and staff concepts and attitudes regarding medication care and to understand better the previously identified inconsistencies. METHODS: We performed a qualitative research based on the grounded theory approach, using semi-structured, in-depth, interviews with patients and staff from the same dialysis unit studied previously, at the Hadassah Medical Center, Jerusalem, Israel. RESULTS: Though all respondents described a seemingly synchronized system of care, repeated questioning revealed that staff distrust patient medication reports. Patients, on their part, felt that their monitoring and supervision were bothersome and belittling. Along with patients, nurses and physicians, we identified a "fourth" factor, which influences medication care - the laboratory tests. They serve both as biological parameters of health, but also as parameters of patient adherence to the prescribed medication regimens. CONCLUSIONS: Participant responses did not clearly resonate with previous findings from the quantitative study. The central role of laboratory tests should be carefully considered by the staff when interacting with patients. An interaction process, less adversarial, centering on the patient attitudes to medication care, might establish better communication, better cooperation and better patient outcomes.

Lower rates of neural tube defects in Israel following folic acid supplementation policy.

Neural tube defects (NTDs) are common and disabling congenital malformations that remain a public health challenge despite prevention efforts. In 2000, The Israeli Ministry of Health published recommendations on daily folic acid (FA) supplementation for women of reproductive age and established a national NTD registry. This study aims to evaluate the long-term impact of the FA supplementation policy on NTD rates in Israel and the need for further intervention. In this descriptive report, we present the rate of NTD-affected pregnancies recorded in the registry between 2000 and 2012, their subtype (anencephaly, spina bifida or other), outcome (live birth, stillbirth or pregnancy termination), ethnic group (Jewish, Bedouin and non-Bedouin Muslim) and years of maternal education. The final analysis included 2374 NTD cases reported between 2000 and 2012, compared with 1,668,073 live births. During this period NTD rates decreased from 20.3 to 11.2 cases per 10,000 live births, a 45% reduction. Reductions were seen in rates of spina bifida, anencephaly and encephalocele. NTD rates decreased in all pregnancy outcomes and in all ethnic groups, though rates among Bedouins remain high. Women with higher levels of education tended to have lower NTD rates, and were more prone to choose termination of an affected pregnancy. Following the institution of FA supplementation in Israel, a substantial reduction was seen in NTD rates. Nonetheless, Israeli NTD rates remain higher than in other developed countries. FA interventions should continue to be vigorously implemented, especially in vulnerable populations. The global success of mandatory fortification of grain strongly advocates its consideration in Israel.

Access-related infections in two haemodialysis units: results of a nine-year intervention and surveillance program.

Background: Access-related infections are a major cause of morbidity and mortality in haemodialysis patients. Our goal was to decrease the rate of these infections by implementing an intervention and surveillance program. Methods: This intervention took place in two haemodialysis units (Units A and B) and was a joint effort by the haemodialysis staff and the unit for infection prevention and control. It included reviewing the work methods and work space, observations on compliance with standard precautions and handling of the vascular access, creating a checklist and a designated kit for handling the vascular access and prospective surveillance of access-related infections. Results: During a nine-year period, the haemodialysis units A and B treated 4471 and 7547 patients (mean number of patients per year: 497 (range 435-556) and 839 (range 777-1055), respectively). For most patients, the procedure was done through an arteriovenous fistula (66.7%, range 50.3-81.5%). The access-related infection rate decreased significantly in both haemodialysis units: from 3 to 0.9% (trend: p < 0.05, linear regression: p < 0.001) in Unit A and from 0.9 to 0.2% (trend: p < 0.05, linear regression: p = 0.01) in Unit B. Conclusions: An intervention which included introduction of a checklist and designated kit, together with ongoing surveillance and feedback, resulted in a significant decrease in the access-related infection rates in both haemodialysis units.